DESCRIPTION (Applicant?s Abstract): Several problems currently limit the application of gene therapy for the treatment for cystic fibrosis lung disease. One significant limitation for most vector systems is the poor efficiency of gene transfer when they are applied to the apical surface of airway epithelia. An attractive approach for overcoming this problem involves substituting (pseudotyping) the envelope glycoproteins of the integrating Feline Immunodeficiency Virus (FIV)-based lentivirus vectors with those of viruses that may target receptors on the apical surface of airway epithelia. To that end, we have screened several envelope proteins from multiple viral families, including amphotropic, xenotropic, VSV-G, RD 114, I OA 1, GALV, Marburg, and Ebola envelope glycoproteins. All pseudotypes except those from the filovirus family were ineffective in transducing cells from the apical surface. However, initial results suggest that the FIV-based vector pseudotyped with the Marburg envelope glycoprotein has the capacity to infect epithelia when applied to the apical surface. These results are encouraging as they suggest that there is no absolute apical barrier to gene transfer with retrovirus vectors. We propose studies that will evaluate the efficiency of the Marburg pseudotyped FIV vector to promote gene transfer across the apical surface of airway epithelia. In addition, we will test-the ability of this pseudotype to correct the CF phenotype in CF epithelia by infecting with a CFTR expressing viral vector. We further propose techniques -to improve the titer as well as demonstrate the in vivo efficacy of this novel vector. The successful completion of these proposed experiments has great implications for the advancement gene therapy.